Purpose of the Core: The Genetic Manipulation Core provides Center investigators with the ability to manipulate gene expression in vitro and in vivo. This Core incorporates a twopronged strategy so that investigators can select the optimal method to meet their needs. The AAV Division provides recombinant viruses for manipulating target expression for instances where acute manipulation is sufficient. For those investigators requiring the ability to manipulate gene expression chronically in vivo, the Core provides bacterial artificial chromosome (BAC) transgene construction. An added advantage of this Core design is that it provides an investigator with the ability to first "test" a particular manipulation using the less expensive viral vector approach and then move to a BACbased approach as appropriate. For example, the Orr group is actively trying to identify the kinases and phosphatases that regulate the phosphorylation of ataxin-1 at Ser776, since this posttranslational modification is thought to regulate the normal function of the protein as well as SCA1 pathogenesis by mutant ataxin-1. Having the ability to modify the activity of enzymes in vivo Figure 2. Floorplans showing Core facilities for the Center (areas enclosed by red boxes), using recombinant viral vectors provides a very useful screen of candidates from cellular and biochemical studies before moving into transgenic mouse studies using a BAC-based approach